Using public control genotype data to increase power and decrease cost of case–control genetic association studies

Genome-wide association (GWA) studies are a powerful approach for identifying novel genetic risk factors associated with human disease. A GWA study typically requires the inclusion of thousands of samples to have sufficient statistical power to detect single nucleotide polymorphisms (SNPs) that are associated with only modest increases in risk of disease given the heavy burden of a multiple test correction that is necessary to maintain valid statistical tests. Low statistical power and the high financial cost of performing a GWA study remains prohibitive for many scientific investigators anxious to perform such a study using their own samples. A number of remedies have been suggested to increase statistical power and decrease cost, including the utilization of free publicly available genotype data and multi-stage genotyping designs. Herein, we compare the statistical power and relative costs of alternative association study designs that use cases and screened controls to study designs that are based only on, or additionally include, free public control genotype data. We describe a novel replication-based two-stage study design, which uses free public control genotype data in the first stage and follow-up genotype data on case-matched controls in the second stage, that preserves many of the advantages inherent when using only an epidemiologically matched set of controls. Specifically, we show that our proposed two-stage design can substantially increase statistical power and decrease cost of performing a GWA study while controlling the type I error rate that can be inflated when using public controls due to differences in ancestry and batch genotype effects

Genetic polymorphisms in CYP17 , CYP3A4 , CYP19A1 , SRD5A2 , IGF-1 , and IGFBP-3 and prostate cancer risk in African-American men: The Flint Men's Health Study

BACKGROUND Association studies have examined the significance of several candidate genes based on biological pathways relevant to prostate carcinogenesis, including both the androgen and insulin-like growth factor pathways. Clinical and epidemiologic evidence suggest that androgens, specifically testosterone and dihydrotestosterone (DHT) are important not only in normal prostate growth but in the pathogenesis of prostate cancer. Similarly, the insulin-like growth factor-1 (IGF-1) signaling pathway regulates both cellular proliferation and apoptosis. Therefore, genes involved in the biosynthesis, activation, metabolism and degradation of androgens and the stimulation of mitogenic and antiapoptotic activities of prostate epithelial cells represent important candidates for affecting the development and progression of prostate cancer. METHODS Using resources from the Flint Men's Health Study, a population-based case control study of African-American men aged 40–79, we evaluated the associations between selected single-nucleotide polymorphisms (SNPs) in the CYP17 , CYP3A4 , CYP19A1 , SDR5A2 , IGF1 , and IGFBP3 genes and prostate cancer diagnosis in 473 men (131 prostate cancer cases and 342 disease-free controls). RESULTS We found a significant association between prostate cancer and selected CYP17 SNP genotypes, with the heterozygous genotype conferring decreased risk. Suggestive evidence for association between IGF1 SNPs and prostate cancer were also found. No significant associations were observed between SNPs in the other genes and prostate cancer. CONCLUSIONS These findings suggest that variation in or around CYP17 and/or IGF1 may be associated with prostate cancer development in the African-American population. Additional studies are needed to determine whether these polymorphisms are indeed associated with prostate cancer risk in African Americans. Prostate 68: 296–305, 2008. © 2007 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/57913/1/20696_ftp.pd

Analysis of the gene coding for the BRCA2-Interacting protein PALB2 in hereditary prostate cancer

BACKGROUND The genetic basis of susceptibility to prostate cancer (PRCA) remains elusive. Mutations in BRCA2 have been associated with increased prostate cancer risk and account for around 2% of young onset (<56 years) prostate cancer cases. PALB2 is a recently identified breast cancer susceptibility gene whose protein is closely associated with BRCA2 and is essential for BRCA2 anchorage to nuclear structures. This functional relationship made PALB2 a candidate PRCA susceptibility gene. METHODS We sequenced PALB2 in probands from 95 PRCA families, 77 of which had two or more cases of early onset PRCA (age at diagnosis <55 years), and the remaining 18 had one case of early onset PRCA and five or more total cases of PRCA. RESULTS Two previously unreported variants, K18R and V925L were identified, neither of which is in a known PALB2 functional domain and both of which are unlikely to be pathogenic. No truncating mutations were identified. CONCLUSIONS These results indicate that deleterious PALB2 mutations are unlikely to play a significant role in hereditary prostate cancer. Prostate 68: 675–678, 2008. © 2008 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58069/1/20729_ftp.pd

A whole genome association study of mother-to-child transmission of HIV in Malawi

Abstract: Background: More than 300,000 children are newly infected with HIV each year, predominantly through mother-to-child transmission (HIV MTCT). Identification of host genetic traits associated with transmission may more clearly explain the mechanisms of HIV MTCT and further the development of a vaccine to protect infants from infection. Associations between transmission and a selection of genes or single nucleotide polymorphisms (SNP)s may give an incomplete picture of HIV MTCT etiology. Thus, this study employed a genome-wide association approach to identify novel variants associated with HIV MTCT. Methods: We conducted a nested case-control study of HIV MTCT using infants of HIV(+) mothers, drawn from a cohort study of malaria and HIV in pregnancy in Blantyre, Malawi. Whole genome scans (650,000 SNPs genotyped using Illumina genotyping assays) were obtained for each infant. Logistic regression was used to evaluate the association between each SNP and HIV MTCT. Results: Genotype results were available for 100 HIV(+) infants (at birth, 6, or 12 weeks) and 126 HIV(-) infants (at birth, 6, and 12 weeks). We identified 9 SNPs within 6 genes with a P-value <5 × 10-5 associated with the risk of transmission, in either unadjusted or adjusted by maternal HIV viral load analyses. Carriers of the rs8069770 variant allele were associated with a lower risk of HIV MTCT (odds ratio = 0.27, 95% confidence interval = 0.14, 0.51), where rs8069770 is located within HS3ST3A1, a gene involved in heparan sulfate biosynthesis. Interesting associations for SNPs located within or near genes involved in pregnancy and development, innate immunological response, or HIV protein interactions were also observed. Conclusions: This study used a genome-wide approach to identify novel variants associated with the risk of HIV MTCT in order to gain new insights into HIV MTCT etiology. Replication of this work using a larger sample size will help us to differentiate true positive findings

Correction: A whole genome association study of mother-to-child transmission of HIV in Malawi

A correction to: Bonnie R Joubert, Ethan M Lange, Nora Franceschini, Victor Mwapasa, Kari E North, Steven R Meshnick andthe NIAID Center for HIV/AIDS Vaccine Immunology. A whole genome association study of mother-to-child transmission of HIV in Malawi. Genome Medicine 2010, 2:17

Age-stratified heritability estimation in the Framingham Heart Study families

The Framingham Heart Study provides a unique source of longitudinal family data related to CVD risk factors. Age-stratified heritability estimates were obtained over three age groups (31–49 years, 50–60 years, and 61–79 years), reflecting the longitudinal nature of the data, for four quantitative traits. Age-adjusted heritability estimates were obtained at a single common time point for the same four quantitative traits. The importance of these groups is that they consist of the same individuals. The highest age-stratified heritability estimate (h(2 )= 0.88 (± 0.06)) was for height in the model adjusting for gender over all three age groups. SBP gave the lowest heritability estimate (h(2 )= 0.15 (± 0.11)) for the 70 age group in the model adjusting for gender, height, BMI, smoker, and drinker. BMI had slightly higher estimates (h(2 )= 0.64 (± 0.11)) in the 40 age group than previously published. The highest age-adjusted heritability estimate (h(2 )= 0.90 (± 0.06)) was for height in the model adjusting for gender. SBP gave the lowest heritability estimate (h(2 )= 0.38 (± 0.09)) for unadjusted model. These results indicate that some common, complex traits may vary little in their genetic architecture over time and suggest that a common set of genes may be contributing to observed variation for these longitudinally collected phenotypes

Identification of a novel germline SPOP mutation in a family with hereditary prostate cancer

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106871/1/pros22818.pd

Genetic Contributors of Incident Stroke in 10,700 African Americans with Hypertension: A Meta-Analysis from the Genetics of Hypertension Associated Treatments and Reasons for Geographic and Racial Differences in Stroke Studies

Background: African Americans (AAs) suffer a higher stroke burden due to hypertension. Identifying genetic contributors to stroke among AAs with hypertension is critical to understanding the genetic basis of the disease, as well as detecting at-risk individuals. Methods: In a population comprising over 10,700 AAs treated for hypertension from the Genetics of Hypertension Associated Treatments (GenHAT) and Reasons for Geographic and Racial Differences in Stroke (REGARDS) studies, we performed an inverse variance-weighted meta-analysis of incident stroke. Additionally, we tested the predictive accuracy of a polygenic risk score (PRS) derived from a European ancestral population in both GenHAT and REGARDS AAs aiming to evaluate cross-ethnic performance. Results: We identified 10 statistically significant (p \u3c 5.00E-08) and 90 additional suggestive (p \u3c 1.00E-06) variants associated with incident stroke in the meta-analysis. Six of the top 10 variants were located in an intergenic region on chromosome 18 (LINC01443-LOC644669). Additional variants of interest were located in or near the COL12A1, SNTG1, PCDH7, TMTC1, and NTM genes. Replication was conducted in the Warfarin Pharmacogenomics Cohort (WPC), and while none of the variants were directly validated, seven intronic variants of NTM proximal to our target variants, had a p-value \u3c5.00E-04 in the WPC. The inclusion of the PRS did not improve the prediction accuracy compared to a reference model adjusting for age, sex, and genetic ancestry in either study and had lower predictive accuracy compared to models accounting for established stroke risk factors. These results demonstrate the necessity for PRS derivation in AAs, particularly for diseases that affect AAs disproportionately. Conclusion: This study highlights biologically plausible genetic determinants for incident stroke in hypertensive AAs. Ultimately, a better understanding of genetic risk factors for stroke in AAs may give new insight into stroke burden and potential clinical tools for those among the highest at risk

Genetic Epidemiology of Body Mass Index and Body Mass Change From Adolescence to Young Adulthood

The complex interplay between genes and environment affecting body mass gain over lifecycle periods of risk is not well understood. We use longitudinal sibling cohort data to examine the role of shared household environment, additive genetic, and shared genetic effects on Body Mass Index (BMI) and BMI change. In the National Longitudinal Study of Adolescent Health, siblings and twin pairs sharing households for ≥10 years as adolescents (N=5524; mean=16.5±1.7 years) were followed into young adulthood (N = 4368; mean=22.4±1.8 years). Using a variance component approach, we quantified genetic and household effects on BMI in siblings and non-siblings sharing household environments over time. Adjusting for race, age, sex, and age by sex interaction, we detected a heritability of 0.43±0.05 for BMI change. Significant household effects were noted during the young adulthood time period only (0.11±0.06). We find evidence for shared genetic effects between BMI and BMI change during adolescence [Genetic Correlation (ρG)=0.61±0.03] and young adulthood (ρG=0.23±0.06). Our findings support a complex etiology of BMI and BMI change

Evidence for an association between prostate cancer and chromosome 8q24 and 10q11 genetic variants in African American men: The flint men's health study

Prostate cancer is the most commonly diagnosed non-skin cancer in men in the United States and the second leading cause of cancer-related mortality. African American men have substantially increased risk of both being diagnosed and dying from the disease. Recent genome-wide genetic association studies have identified a number of common single nucleotide genetic polymorphisms (SNPs) that are associated with prostate cancer in men of European descent. Only a small number of studies have evaluated the association between these genetic variants and prostate cancer in African Americans